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The tissue diagnostic instrument
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View: Figures


Image of FIG. 1.

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FIG. 1.

The TDI. (a) The TDI can measure mechanical properties of tissues under test even if they are covered with skin and other soft tissues because it has a probe assembly that can be inserted subcutaneously into the tissue under test. (b) It can be handheld and is connected to a computer for data generation, acquisition, and processing. In this photo it is being used to measure differences in the mechanical properties of fruit and gel in a snack food. (c) A probe assembly for the TDI consists of a test probe, which moves displacements of the order of relative to the reference probe. The reference probe serves to shield the test probe from the influence of the skin and soft tissue that must be penetrated to reach the tissue under test. Type D probes are good for very soft tissue, such as the murine breast tissue in Fig. 3. Type N probes are good for stiffer tissue, such as the spinal disk tissue in Fig. 2. The screw at the top of the TDI (a) can adjust the compliance of the TDI, as discussed in the supplementary material.

Image of FIG. 2.

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FIG. 2.

Demonstration of the ability of the TDI to distinguish between the annulus and nucleus of a human intervertebral disk. (a) X-ray image of transverse view of a cadaver lumbar motion segment L12 with test probe located in annulus. (b) Similar view with probe centered in the nucleus. (c) Force vs displacement curve measured by the TDI during a cyclic load cycle (4 Hz) in the annulus. (d) Force vs displacement curve measured in the nucleus. Note that the annulus is much stiffer (higher slope) and dissipates more energy (higher area enclosed by the curve). (e) Histogram comparing the average least-squares slope for ten cycles in the annulus vs in the nucleus. (f) Histogram comparing the average energy dissipation for ten measurements in the annulus vs in the nucleus ( vs ; ). The error bars indicate standard deviation for the ten measurements within the annulus and within the nucleus in the disk.

Image of FIG. 3.

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FIG. 3.

Demonstration of the ability of the TDI to distinguish between normal mammary glands and tumors. Hematoxylin and eosin (H&E) staining of (a) the representative normal FVB murine mammary gland and (b) the matched malignant mammary gland that were tested in this experiment. (c) The mammary tumors have significantly higher slopes, a measure of elasticity, for both the thoracic # 2/3 and the inguinal #4 tissues. (d) The mammary tumors have significantly higher energy dissipation for the thoracic # 2/3 tissue , but the difference for the inguinal # 4 tumor was not significant. Histogram comparing (e) the elastic modulus and (f) the loss modulus, as measured by rheology, for the normal mammary glands and mammary tumors after the TDI measurements (two subregions for each mammary gland, ten measurements for each region). Note that the results for elasticity and loss modulus for the two techniques reproduce the same general trends. The error bars in the measurements indicate standard deviation for all the measurements.

Image of FIG. 4.

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FIG. 4.

Demonstration of the ability of the TDI to distinguish differences in moduli of stratified materials such as cartilage. (a) The elastic modulus can be determined with the type V probe assembly that indents soft materials rather than penetrating them, as above. (b) PA gels with elastic moduli in the range previously reported for cartilage (0.2–1 MPa) were used to validate the TDI relative to other established methods, including atomic force microscopy, nanoindentation, and bulk stress relaxation. PA gel moduli increased dose-dependently with cross-linker concentration . (c) To construct a stratified elastic modulus gel, a 0.2 mm thick layer of “compliant” PA gel was poured over a prepolymerized 1 mm thick “stiff” PA gel. (d) The force vs displacement curve produced by the TDI revealed two distinct slopes on the loading curve for the stratified gels. Each slope of the composite gel matches the corresponding slopes for homogeneous 0.5% and 2% PA gel, demonstrating the capability to analyze stratified materials, such as cartilage. (e) A schematic of the indentation tests performed on cartilage, which were performed in hydrated conditions with phosphate buffered saline. (f) Using similar test conditions, the TDI easily distinguished between young cadaveric cartilage and aged degenerated cartilage measured in situ.

Image of FIG. 5.

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FIG. 5.

Demonstration of the ability of the TDI to measure the elastic modulus and hardness of human dentin to quantify the properties of the dentin left in a tooth cavity after each of multiple excavations and finally preparation. (a) The probe assembly for these measurements was designed to indent the hard tissue. The reference probe was a hypodermic needle that rested on the surface under test. The test probe was sharpened into a 90° cone with a radius at the end (drawing by Haykaz Mkrtchyan). (b) The teeth after the various excavations and finally preparation. At each successive stage of excavation and preparation more dentin was removed from the cavity. [(c) and (d)] The elastic modulus and hardness of the dentin remaining in the cavity was significantly less than that of healthy dentin. The error bars indicate standard deviation of the ten measurements that were taken on each of the five teeth (a total of 50 measurements). Note that the elastic modulus of the healthy dentin is over 10 GPa, over seven orders of magnitude greater than the normal mammary glands (Fig. 3), demonstrating the range of the TDI.

Image of FIG. 6.

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FIG. 6.

Demonstration of the ability of the TDI to do measurements on a living patient. (a) The probe assembly of the TDI is lowered by a physician (A.D.P.) to penetrate the skin and soft tissue covering the tibia of the patient (D.B.) after the test site has been sterilized and locally anesthetized. (b) Close up of the physician’s hand on the probe assembly as he lowers it to the bone surface. (c) Representative force vs distance curves measured on the bone of the patient. This patient and the other patients tested to date experienced neither pain nor complications with the procedure. The most important parameter is the indentation distance increase (IDI) defined in the image as the increase in indentation distance from the first cycle to the last. In model systems the IDI is greater for more easily fractured bone. Other parameters such as the creep at nearly constant force (the plateau on the top of the curves), the elastic modulus, the energy dissipation, and the hardness can also be determined from analysis of the force vs distance curves.


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Tissuemechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument (TDI), a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection.


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752b84549af89a08dbdd7fdb8b9568b5 journal.articlezxybnytfddd
Scitation: The tissue diagnostic instrument